There are number of pharmaceutical drugs that are poorly soluble or insoluble in aqueous solutions. Such drugs provide challenges in terms of having poor oral bioavailability or in terms of formulating them for drug delivery especially through the intravenous route. If a drug is intravenously administered, particles must be small enough to safely pass through capillaries without causing emboli. For intravenous administration, it is recognized as safe to administer drugs in the form of solution, emulsion, liposomes, nanodispersions and the like. Another requirement that should be met while formulating a drug delivery system especially for hydrophobic drugs is that the formulation should be physically stable with no substantial aggregation or crystallization of the drug or change in appearance of the formulation on storage at room temperature for desired period of time.
An example of a poorly soluble drug includes taxane derivatives which are well known for their anticancer activity. A taxane derivative or a taxoid is a complex diterpenoid natural product derived principally from the bark of the Western Yew, Taxus brevifolia and essentially has a taxane skeleton. Taxanes have been used to produce various chemotherapeutic drugs. Currently two taxane derivatives paclitaxel and docetaxel are available commercially as potent anti-tumor agents.
The taxane derivatives exhibit very poor solubility in water and in most pharmaceutically acceptable solvents thus limiting their administration to patients. Due to this unfavorable intrinsic property, TAXOL injection, the commercially marketed paclitaxel injection is formulated as a non-aqueous solution in Cremophor™ EL (a polyethoxylated castor oil) and dehydrated alcohol. However, use of solubilizer like Cremophor™ EL in large amounts lead to various adverse effects such as serious or fatal hypersensitive and hypertensive reactions, brady arrhythmia, anemia, neutropenia and/or peripheral neuropathy. Therefore all patients receiving paclitaxel are premedicated with steroids, antihistamines and H2 receptor antagonists and then paclitaxel is only infused very slowly over a period of at least 3 hours or more.
In view of these problems associated with Taxol formulations, researchers have tried to prepare taxol formulations without using Cremophor EL.
U.S. Pat. No. 6,537,579 describes compositions of substantially water insoluble pharmacologically active agents such as paclitaxel, in which the pharmacologically active agent exists in the form of suspended particles coated with protein (which acts as a stabilizing agent). In particular, protein and pharmacologically active agent in a biocompatible dispersing medium are subjected to high shear, in the absence of any conventional surfactants, and also in the absence of any polymeric core material for the particles. The procedure yields particles with a diameter of less than about 1 micron. The particulate system produced according to the invention can be converted into a redispersible dry powder comprising nanoparticles of water-insoluble drug coated with a protein, and free protein to which molecules of the pharmacological agent are bound.
U.S. Pat. No. 6,017,948 relates to a composition comprising paclitaxel in the form of a solution of paclitaxel in a pharmaceutically acceptable, water-miscible, non-aqueous solvent (like N-methylpyrrolidone) and further comprising a pharmaceutically acceptable solubilizer (such as triacetin), with the provision that polyethoxylated castor oil (Cremophor) is excluded from the composition. In preferred embodiments, a large amount of solvent i.e. 4000 mg of NMP (example 1) or combination of 2000 mg of NMP and 2000 mg of ethanol (example2) were used to solubilize 10 mg of paclitaxel under moderate agitation. If therapeutically effective amount of drug is delivered through such compositions, it will be associated with entry of excessive amounts of ethanol, non-aqueous solvents or solubilizers in the body.
U.S. Pat. No. 6,046,230 relates to a stable injection formulation containing paclitaxel and two solubilizers—oxyethylene sorbitol oleate and (oxyethylene glycol)15-20 fatty acid monoester along with additional components such as povidone and polyethylene glycol. The main solubilizer used in the formulation polyethoxylated sorbitol oleic polyester which is an ethylene oxide addition product of palm olein-derived oleic acid has an inherent property of getting solidified at temperatures below 10° C., making it unsuitable for solubilizing paclitaxel when used alone. However when combined with an auxillary solubilizer polyethylene glycol mono fatty acid ester, the two solubilizers together exhibit good solubility in water and in anhydrous alcohol and they stay in fluid phase even at low temperatures. So, use of the two solubilizers together is mandatory. Also it is an essential criterion that HLB value of the solubilizers which meet the desired characteristics should be as high as 15 but not less than 13. The resulting formulation is a solution.
PCT Application no. WO 2006/133510 discloses a liquid pharmaceutical formulation for parenteral administration comprising docetaxel or a pharmaceutically acceptable salt thereof; one or more glycols and a pharmaceutically acceptable non-aqueous solvent system, wherein the formulation has a pH meter reading in the range of from 2.5 to 7.0. The embodiments of the invention involve use of very high amount of surfactants (about 25% v/v of polysorbate 80 or 30% v/v of Cremophor) which in turn can lead to toxic side effects. The application does not disclose the efficacy and toxicity profile of the formulations. Further the formulation disclosed by the '510 application is a solution of drug in a non-aqueous solvent system which on admixture with an infusion diluent (0.9% NaCl or 5% Dextrose solution) produces an infusion solution. A novel drug delivery system or nanodispersion is not formed anywhere in the process. Also the stability of the formulation solutions after diluting with infusion diluent is of very short period of about 4 to 6 hours which can limit its administration efficiency.
US2002/0058060 (hereinafter referred to as patent application '060) discloses liposomes containing hydrophobic substances and two phospholipids with different phase transition temperatures and liposome forming materials like cholesterol and hydrophilic polymer modified lipids. The ratio of the drug to the phospholipids and the liposome forming materials is varied to get different liposomal formulations. The patent application '060 indicates several attempts to formulate liposomes of taxanes which have elevated drug:lipid ratio, by using two specified class of phospholipids, so that total amount of lipid used is reduced, as injection of excessive amount of lipids in the body leads to certain extent of toxicity.
Thus it is evident from the prior art that the major problem associated with formulating a taxane composition is hydrophobicity of taxanes, which                (a) makes it difficult to formulate a composition which contains solubilized form of the drug and which is stable, without any substantial aggregation or crystallization of the drug or change in appearance of the formulation till a desired period of time        (b) necessitates the use of large amount of solubilizers, phospholipids and surfactants.        
Also, toxicity studies of TAXOL (marketed solution of paclitaxel in Cremophor and Alcohol) shows a LD50 value of 7.5-12.0 mg/kg as disclosed in U.S. Pat. No. 6,753,006 which is low, indicating that the drug administered in the form of solution has very low therapeutic index and even a moderate dose may show serious side effects and toxic reactions.
Thus there exists a need for an injectable formulation of a taxane derivative which                (a) avoids the use of large amount of excipients,        (b) avoids the use of Cremophor,        (c) delivers the drug through a novel delivery system, which shows increased LD50 value, minimizing the toxic side effects associated with the administration of the drug in solution form and        (e) overcomes the limitations of the drug associated with its hydrophobic nature and is stable with no substantial aggregation or crystallization of the drug or change in appearance of the formulation, for the desired period of time during administration and during storage.        
We have developed a nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle comprising a water miscible solvent and water, said nanoparticles comprising a taxane derivative, a polymer and very low amount of surfactants. The present invention provides a formulation which avoids the use of Cremophor, involves the use of much reduced amounts of additives (phospholipids) and delivers the drug in the form of nanoparticles, thus minimizing the toxic reactions and side effects associated with the administration of the drug. The LD50 value observed for formulations of the present invention is 342.5 mg/kg which is much greater than the LD50 value of 7.5-12.0 mg/kg of marketed TAXOL® solution as disclosed in U.S. Pat. No. 6,753,006. Also the formulation of the present invention is stable, with no substantial aggregation or crystallization of the drug or change in appearance of the formulation, for the desired period of time during administration and during storage.